SK278895B6 - Use of ketoconazole - Google Patents

Abstract

This patent describes application of ketoconazole or its salts suitable from pharmaceutical point of view to the production of drugs used for reversion, termination or retardation of alopecia course and / or for improvement of hair quality. Ketoconazole is a generic identification of the compound called (+/-)-cis-1-acetyl-4-(4-(2-(2,4-dichlorophenyl)-2-(1H- -imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)- -phenyl)piperazine.

Description

Technical field

The invention relates to the use of ketoconazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament with a new indication.

BACKGROUND OF THE INVENTION

A healthy, dense and even hair stand is usually considered an important aesthetic aspect of the human body. Hair loss or any imperfection in hair quality is therefore considered a highly undesirable feature of the physical exterior.

The fact that the majority of the male population is genetically predisposed to progressive hair loss and that hitherto treatments are scarce and few individuals respond effectively to them broadly illustrates the scale of the problem. Thus, there is a continuing need for further treatments that effectively restore hair growth or arrest or slow hair loss, and improve hair quality.

The ketoconazole used according to the invention is a known antifungal agent and its preparation and pharmacological properties are described in US 4,335,125.

Ketoconazole is a generic designation of (+) - cis-1-acetyl-4- (4 - ((2- (2,4-dichlorophenyl)) -2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane) (4-yl) methoxy) phenyl) piperazine, which may be represented by the formula

SUMMARY OF THE INVENTION

Surprisingly, it has now been found that ketoconazole can effectively restore hair growth or stop or slow down hair loss, phenomena occurring in alopecia. In addition, ketoconazole has a beneficial effect on hair quality.

It is an object of the invention to use ketoconazole or a pharmaceutically acceptable salt thereof for the manufacture of medicaments for reversing, arresting or slowing down the course of alopecia and / or for improving hair quality.

Ketoconazole can be used as such or in the form of a pharmaceutically acceptable acid addition salt. Such salts can be readily prepared by treating the free base with the appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, for example hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. or organic acids such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethanedioic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2 , 3-dihydroxy-butanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4

-amino-2-hydroxybenzoic acid and the like. The term acid addition salts as used herein also includes the solvates that ketoconazole or its addition salt can form. Examples of such solvates are, for example, hydrates, alcoholates and the like.

Alopecia as used herein refers to hair loss from the scalp, but also to chin. In particular, the term alopecia is used to refer to androgenic alopecia, or to male baldness, which is characterized by a gradual diffuse symmetrical hair loss from the scalp, which usually begins at the front of the scalp and gradually extends to the top. Finally, only the perimeter strip covering the temples and nape of the scalp remains.

Since alopecia is a disease that is currently difficult to treat, if not impossible at all, the finding that ketoconazole can be effectively administered in the treatment of patients suffering from alopecia, particularly those with early androgenic alopecia, is very surprising. In this regard, effective treatment is understood to mean that ketoconazole causes hair growth to be restored, stops or slows hair loss, and improves hair quality, especially its thickness, which can be determined by measuring the hair caliber. Early androgenic alopecia refers to male baldness classified as type I, II, III, IV or V on the Hamiltonian scale.

Hair quality in this specification means desirable physical properties of the hair, such as its strength, density, thickness, uniformity and sensitivity. For example, poor hair quality can be manifested by splitting or breaking. Hair thickness is usually expressed as hair diameter or hair caliber. Density refers to the number of hairs per unit area, while uniformity refers to the stability or gradual change in hair density in adjacent scalp areas. Hair sensitivity means the presence of tactile sense in hair.

Ketoconazole and its addition salts are preferably applied to the affected areas of the scalp or chin in the form of suitable formulations, in particular formulations typically used for topical administration of medicaments or cosmetics. These preparations contain the active ingredient, ketoconazole, preferably at a concentration of 0.1 to 5% (w / v). In addition, they may contain any dermatologically acceptable carrier. The form of preparation may be varied, for example as liquids, for example solutions or suspensions in aqueous or oily media, or semi-liquid preparations, for example creams, hydrogels, paste gels, ointments, elixirs, and the like.

Other suitable formulations include cosmetic-type formulations such as toilet lotions, hardened preparations, cosmetic liquids, lotions or emulsion cosmetic liquids and shampoos. These formulations contain, in addition to the active ingredient ketoconazole, other ingredients commonly used in such formulations. Examples of such additional ingredients are oils, fats, waxes, surfactants, humectants, penetration enhancers, thickeners, lipid absorbents, antioxidants, viscosity stabilizers, chelating agents, buffers, preservatives, perfumes, colorants, lower alkanols, and the like. . If desired, additional active ingredients, for example anti-inflammatory agents, antibacterial agents, antifungal agents, disinfectants, vitamins, sun filters, antibiotics or anti-dandruff agents, may be added to these compositions.

Very interesting preparations are cosmetic liquids and shampoos, which usually contain 0.2 to 2.5%, in particular 2% of ketoconazole.

Said cosmetic liquids are novel substances that have been especially developed for use in the present invention. Such cosmetic liquids generally contain 0.2 to 2.5%, in particular 2% (w / v) of the active ingredient ketoconazole; propylene carbonate in an amount of from 20 to 40%, in particular from 20 to 30% and in particular about 25% (w / v), ethanol in an amount of from 25 to 50%, in particular from 25 to 35% and in particular about 28% (w / v) ) and, where appropriate, any other ingredients listed in such preparations. The rest of the cosmetic liquid is water.

Specific examples of such formulations include those comprising cyclodextrin or a derivative thereof. The term cyclodextrin or a derivative thereof is used for the topically acceptable unsubstituted and substituted cyclodextrins known in the art, such as alpha, beta or gamma-cyclodextrin and derivatives thereof, such as ethers, polyethers and mixed ethers.

In the preparation of cyclodextrin-based preparations, ketoconazole is added to a solution of cyclodextrin in water, preferably with vigorous stirring, and then the remaining components are added. The amount of cyclodextrin in the final formulation is about 2 to 40%, especially about 2.5 to 25%, and especially about 5 to 20%.

Other particular formulations suitable for use in the methods of the invention include those in which the active ingredient, ketoconazole, is mixed into a liposome-containing composition. Various types of liposomes can be used, such as coarse (multilayer) liposomes or monolayer liposomes and the like, which are formed, for example, with phosphatidylcholines, ethanolamines, serines, spmgomyelins, cardiolipins, plasmalogens, phosphatidic acids, and cerebioside. The viscosity of liposomes can be increased by the addition of one or more thickeners such as xanthan gum, hydroxypropylcellulose, hydroxymethylcellulose and mixtures thereof. The aqueous component may consist of water, optionally in admixture with electrolytes, buffers and other additives such as preservatives. Preferred electrolytes include calcium chloride, sodium chloride and potassium chloride. The organic component may consist of solvents such as ethanol, glycerol, propylene glycol, polyethylene glycol, and a suitable phospholipid such as lecithin, phosphatidylcholine, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, lysophosphatidide, lysophosphatidide, and lysophosphatidide. Other lipophilic additives that can be added to selectively modify the properties of liposomes include, for example, stearylamine, phosphatidylic acid, tocopherol, cholesterol, lanolin, and the like.

In the manufacture of ointments, creams, toilet waters, lotions and the like. usually a perfect mixture of 0.1 to 10%, preferably 0.1 to 5% and most preferably 0.2 to 2.5% of the active ingredient, ketoconazole or its acid addition salt, with a carrier suitable for the preparations to be applied is prepared for skin and hair. In order to facilitate the preparation of high-quality formulations, ketoconazole and, optionally, other solid components are used in the form of finely divided particles, preferably in the form of micronized particles. In ointments or creams, a suitable carrier is, for example, a mixture of 1 to 20%, preferably 5 to 15% humectant, 0.1 to 10%, preferably 0.5 to 5% thickener and water, and a mixture of 70 to 99%, preferably 20 to 95% 0 to 20%, preferably 2.5 to 15% fat or 80 to 99.9%, preferably 90 to 99% thickening agent or a mixture of 5 to 15% surfactant, 2 to 15% humectant, 0 to 20% 80% oil, very small (below 2%) preservative, colorant and / or perfume and water. In toilet water, a suitable carrier is, for example, a mixture of 2 to 10% lower alcohol, 0.1 to 10%, preferably 0.5 to 1% surfactant, 1 to 20%, preferably 3 to 7% humectant, 0 to 5% buffer , water, and minor amounts (below 2%) of a preservative, colorant and / or perfume. In the lotion, the carrier typically comprises 10 to 50% oil, 1 to 10% surfactant, 50 to 80% water and 0 to 3% preservative and / or perfume. Other active ingredients may be added in an amount of from 0.005 to 0.5%, preferably from 0.01 to 0.1%. In all the above preparations, the percentages are by weight. Any of the ingredients used in similar pharmaceutical or cosmetic compositions may be added as humectants, surfactants, oils or other active ingredients, etc., as mentioned in the above calculation. If one or more of the ingredients is present in the predominant amounts in the said compositions, the other ingredients naturally cannot be present at the maximum concentrations indicated and therefore constitute a residue of up to 100%.

Micronized forms of ketoconazole, i. j. The particles are in the form of particles having an average particle size of less than 10 µm, as the high specific surface area facilitates dissolution.

Said liquid preparations may conveniently be packaged in any dosage container adapted for topical administration. The compositions of the invention and in particular the novel cosmetic liquids of the invention are preferably administered in the form of aerosols. A propellant such as compressed nitrogen or carbon dioxide or a mechanical atomizer is used.

In a preferred embodiment, the composition is used in the form of a spray package comprising said cosmetic liquid and carbon dioxide as a propellant.

The ketoconazole-containing formulations are applied topically to the site to be treated at regular intervals, as required or desired, for example at or after each head wash. The duration of treatment depends on the type, extent and severity of the disease to be treated, and on the frequency of administration. No special precautions should be followed except those normally observed when applying medicines to the skin or hair.

DETAILED DESCRIPTION OF THE INVENTION

A) Examples of preparations

Example 1

2% ketoconazole cream ketoconazole20 mg propylene glycol 200 mg stearyl alcohol75 mg cetyl alcohol 20 mg sorbitan monostearate 20 mg polysorbate 6015 mg isopropyl myristate 10 mg sodium sulfite anhydrous2 mg polysorbate 801 mg purified water q. with. ad1 g

SK 278895-6

Stearyl alcohol, cetyl alcohol, sorbitan monostearate and isopropyl myristate are placed in a duplicate vessel and the mixture is heated until it melts. The resulting mixture is added to a separately prepared mixture of purified water, propylene glycol and polysorbate 60, melting at 70-75 ° C, using a homogenizer for mixing liquids. The resulting emulsion is cooled to about 25 ° C with stirring. A solution of ketoconazole, polysorbate 80 and purified water, a solution of anhydrous sodium sulfite in purified water, is then added to the emulsion with continued stirring. The resulting cream is homogenized and filled into tubes.

Example 2

2% topical gel

very fine ketoconazole 2 g phosphatidylcholine 20 g cholesterol 5 g ethanol 10 g methylparaben 0.2 g propyl 0,02 g disodium edetate 0.15 g sodium chloride 0.3 g hydroxypropyl 1.5 g purified water up to 100 g

ketoconazole 20mg hydroxypropyl-beta-cyclodextrin 200mg propylene glycol 50mg ethyl alcohol 95% (v / v) 50mg carrageenan P J10 mg hydrochloric acid q.s. until dissolved sodium hydroxide q.s. to pH 6.0 purified water q.s. up to 1 g

The mixture of very fine ketoconazole, phosphatidylcholine, cholesterol and ethyl alcohol is stirred and heated to 55-60 ° C until complete dissolution and the resulting solution is added to a solution of methylparaben, propylparaben, disodium edetate and sodium chloride in purified water. The mixture is homogenized during the addition. Hydroxypropylmethylcellulose in purified water is then added and stirring is continued until swelling is complete.

Example 5

2% liposomal formulation

To a solution of hydroxypropyl beta-cyclodextrin in purified water is added ketoconazole with stirring. Hydrochloric acid is added until complete dissolution and then the pH is adjusted to 6.0 with sodium hydroxide. The resulting solution was added to a dispersion of carrageenan PJ in propylene glycol with stirring. Then the mixture is stirred slowly, heated to 50 ° C, allowed to cool to about 35 ° C and ethyl alcohol is added. Finally, the remainder of the purified water is added and the mixture is stirred until homogeneous.

Example 3 very fine ketoconazole2 g phosphatidylcholine10 g cholesterol1 g ethyl alcohol7,5 g hydroxypropylmethylcellulose 1.5 g sodium hydroxide (IN) to pH 5.0 purified water to 100g

2% topical cream

100 mg mg mg mg mg mg mg

qs until dissolved

qs to pH 6.0

qs up to 1 g

The mixture of phosphatidylcholine and cholesterol in ethyl alcohol is stirred and heated to 40 ° C until complete dissolution. The very fine ketoconazole is dissolved in purified water with stirring and heating to 40 ° C. The alcoholic solution was added to the aqueous solution over a further 10 minutes of homogenization. Hydroxypropylmethylcellulose in purified water is then added with stirring and stirring is continued until complete swelling. The pH of the resulting solution was adjusted to 5.0 with 1 N sodium hydroxide, and the resulting mixture was diluted with residual purified water.

Example 6

2% cosmetic liquid for scalp very fine ketoconazole propylene carbonate ethyl alcohol purified water mg

241.4 mg

282.8 mg q.s. ad 1 ml

The very fine ketoconazole is stirred in a mixture of propylene carbonate and ethanol until completely dissolved.

ketoconazole 20 mg hydroxypropyl beta-cyclodextrin 200 mg mineral oil stearyl alcohol cetyl alcohol glycerol monostearate glycerol sorbate 60 polysorbate 60 hydrochloric acid sodium hydroxide purified water

To a solution of hydroxypropyl beta-cyclodextrin in purified water is added ketoconazole with stirring. Hydrochloric acid is then added until complete dissolution followed by sodium hydroxide to adjust the pH to 6.0. While stirring, glycerol and polysorbate 60 are added and the mixture is heated to 70 ° C. The resulting mixture was added to a mixture of mineral oil, stearyl alcohol, cetyl alcohol, stearyl monostearate and sorbate 60 at 70 ° C with slow stirring. After cooling to a temperature below 25 ° C, the remainder of the purified water is added and the mixture is stirred until homogeneous.

The resulting solution is diluted with purified water to the desired concentration. The resulting solution is filled with suitable vials or spray containers.

B) Clinical example

Example 4

2% liposomal formulation

Example 7

The usefulness of ketoconazole for the treatment of alopecia can be demonstrated as follows: 27 men (22 to 31 years) affected by Hamilton grade II androgenic alopecia use Nizoral shampoo ⁽²⁾ containing 2% ketoconazole for 60 weeks as often as shampooing is considered trial. necessary. The frequency of shampooing is 2-4 times a week. Every 12 weeks, hair trichograms are recorded in the areas at the periphery of the bald. Calculate the hair (piles) index Ip by determining the proportion of hair (A in%) that is in the anagenic phase of the hair cycle and multiplying this by the mean hair diameter (C in / µm):

Ip-A x C

In adult men who are not affected by androgenic alopecia, the Ip value is greater than 60, in 27 volunteers the mean Ip value at the start of the trial was 18, but changed only slightly during the first 24 weeks of treatment. A significant increase in the Ip value according to the U-test (P 0.05) occurred at 36 weeks. During treatment, a clear improvement in the sawmill index was observed, which reached approximately twice its original value after 60 weeks. These results show that ketoconazole has a truly beneficial effect in the treatment of alopecia and improves overall hair quality.

Claims (1)

PATENT CLAIMS Use of ketoconazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for reversing, arresting or slowing down the course of alopecia and / or for improving hair quality.